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the inherent tolerance of the equipment and its components. It is therefore logical to say that variability in raw materials married with a static batch process with inherent variability in process equipment produces variable product. This is on the basis that a static batch process produces product by following a fixed recipe with fixed set-points.
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It would be acceptable to consider that raw materials used to manufacture pharmaceutical products can vary in their attributes e.g. moisture content, crystal structure etc. It would also be acceptable to consider that manufacturing equipment does not always operate in exactly the same fashion due to
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PAT is a term used for describing a broader change in pharmaceutical manufacturing from static batch manufacturing to a more dynamic approach. It involves defining the
Critical Process Parameters (CPPs) of the equipment used to make the product, which affect the Critical Quality Attributes (CQAs) of
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tools: paper systems or software packages which accumulate
Quality Control data acquired over time for specific processes with the aim of defining process weaknesses and implementing and monitoring process improvement initiatives. These products may be the same or separated from the statistical
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This mechanism for producing consistent product quality & reducing waste presents a good case for utilising continuous manufacturing technologies. The control of a steady state process when you understand the upstream & downstream effects is an easier task as common cause variability is
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The FDA has outlined a regulatory framework for PAT implementation. With this framework – according to Hinz – the FDA tries to motivate the pharmaceutical industry to improve the production process. Because of the tight regulatory requirements and the long development time for a new drug, the
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The concept aims at understanding the processes by defining their CPPs, and accordingly monitoring them in a timely manner (preferably in-line or on-line) and thus being more efficient in testing while at the same time reducing over-processing, enhancing consistency and minimizing rejects.
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Currently NIR spectroscopy applications dominate the PAT projects. A possible next-generation solution is Energy
Dispersive X-Ray Diffraction (EDXRD). For a detailed review of PAT tools see Scott, or Roggo. For an example of application see Gendre.
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encourages process control based on the real-time acquired data, a small part of PAT applications goes beyond monitoring the processes and follows the PACT (‘Process
Analytically Controlled Technology’) approach.
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The challenge to date with PAT for pharmaceutical manufacturers is knowing how to start. A common problem is picking a complex process and getting mired in the challenge of collecting and analyzing the data.
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the product and then controlling these CPPs within defined limits. This allows manufacturers to produce products with consistent quality and also helps to reduce waste & overall costs.
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With this in mind the PAT drive is to have a dynamic manufacturing process that compensates for variability both in raw materials & equipment to produce a consistent product.
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Nagy, B; et al. (2017). "In-line Raman spectroscopic monitoring and feedback control of a continuous twin-screw pharmaceutical powder blending and tableting process".
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Roggo, Y.; Chalus, P.; Maurer, L.; Lemamartinez, C.; Edmond, A.; Jent, N. (2007). "A review of near infrared spectroscopy and chemometrics in pharmaceutical technologies".
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Process analytical chemistry (PAC) tools: in-line and on-line analytical instruments used to measure those parameters that have been defined as CPP. These include mainly
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Generally, the PAT initiative from FDA is only one topic within the broader initiative of "Pharmaceutical cGMPs for the 21st century – A risk based approach".
344:"Development of a Process Analytical Technology (PAT) for in-line monitoring of film thickness and mass of coating materials during a pan coating operation"
207:(DoE). This is because analysis of the process data is a key to understand the process and keep it under multivariate statistical control.
226:, Guidance for industry: PAT – A framework for innovative pharmaceutical development, manufacturing and quality assurance; September 2004
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238:, Process analytical technologies in the pharmaceutical industry: the FDA's PAT initiative; Anal Bioanal Chem, Vol 384, p1036-1042, 2006
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Scott, B.; Wilcock, A. (2006). "Process analytical technology in the pharmaceutical industry: A toolkit for continuous improvement".
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Gendre, C.; Genty, M.; Boiret, M.; Julien, M.; Meunier, L. C.; Lecoq, O.; Baron, M.; Chaminade, P.; Péan, J. M. (2011).
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27:(FDA) as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of
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Multivariate data acquisition and data analysis tools: usually advanced software packages which aid in
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In order to implement a successful PAT project, a combination of three main PAT tools is essential:
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250:, Pharmaceutical cGMPs for the 21st century – A risk based approach; Final Report, September 2004
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Determine what information is easily collected and accessible through current instrumentation.
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Picking a simple process. (Think water for injection (WFI) or building monitoring system (BMS)
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263:, December 2006/January 2007, page 81. Colorado, United States: E.L.F. Publications, Inc.
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The following criteria serve as a basic framework for successful PAT roll-outs: (From
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production technology is "frozen" at the time of conducting phase-2 clinical trials.
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Fundamental to process analytical technology (PAT) initiatives are the basics of
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All details and nuances are well understood and explained for that process.
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Evaluating the tools available for reading and synchronizing the data.
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Understanding the appropriate intervals for collecting that data.
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428:EMEA: Inspections – Process Analytical Technology
309:Journal of Pharmaceutical and Biomedical Analysis
438:Process Analytical Technology Resource Website
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351:European Journal of Pharmaceutical Sciences
23:) has been defined by the United States
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386:International Journal of Pharmaceutics
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159:The long-term goals of PAT are to:
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178:facilitate continuous processing
175:improve energy and material use
172:increase automation and control
163:reduce production cycling time
59:easier to define and monitor.
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398:10.1016/j.ijpharm.2017.07.041
17:Process analytical technology
166:prevent rejection of batches
25:Food and Drug Administration
33:critical quality attributes
29:critical process parameters
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443:PAT Seminars & Events
363:10.1016/j.ejps.2011.04.017
321:10.1016/j.jpba.2007.03.023
125:near infrared spectroscopy
127:(NIRS); but also include
169:enable real time release
31:(CPP) which affect the
261:Healthcare Distributor
143:Continuous improvement
205:design of experiments
201:multivariate analysis
150:analysis tools above.
118:design of experiments
188:FDA's PAT initiative
147:knowledge management
423:FDA: PAT Initiative
458:Drug manufacturing
433:ASTM PAT Committee
133:Raman spectroscopy
75:PAT implementation
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137:fiber optics
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85:A PAT Primer
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203:(MVDA) and
139:and others.
452:Categories
417:References
195:MVA in PAT
129:biosensors
50:The basics
269:833048096
211:Footnotes
108:PAT tools
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371:21569842
329:17482417
294:17089677
145:and/or
35:(CQA).
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347:(PDF)
402:PMID
367:PMID
325:PMID
290:PMID
265:OCLC
236:Hinz
394:doi
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359:doi
317:doi
248:FDA
224:FDA
21:PAT
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